Lesion Genotype Modifies High-Fat Diet Effects on Endometriosis Development in Mice.

Melissa E Heard-Lipsmeyer,Iad Alhallak,Stepan B Melnyk,Rosalia C M Simmen,Frank A Simmen

doi:10.3389/fphys.2021.702674

Abstract

Endometriosis is a chronic, estrogen-dependent gynecologic disorder that affects reproductive-aged women and to a lesser extent, post-menopausal women on hormone therapy. The condition is associated with systemic and local immune dysfunctions. While its underlying mechanisms remain poorly understood, endometriosis has a genetic component and propensity for the disease is subject to environmental, nutritional, and lifestyle influences. Previously, we showed that high-fat diet (HFD) increased ectopic lesion numbers, concurrent with systemic and peritoneal changes in inflammatory and oxidative stress status, in immunocompetent recipient mice ip administered with endometrial fragments null for Krüppel-like factor 9 gene. Herein, we determined whether HFD modifies lesion parameters, when recipient peritoneal environment is challenged with ectopic wild-type (WT) endometrial fragments, the latter simulating retrograde menstruation common in women during the menstrual period. WT endometrium-recipient mice fed HFD (45% kcal from fat) showed reduced lesion incidence, numbers, and volumes, in the absence of changes in systemic ovarian steroid hormone and insulin levels, relative to those fed the control diet (CD, 17% kcal from fat). Lesions from HFD- and CD-fed recipients demonstrated comparable gene expression for steroid hormone receptors (Esr and Pgr) and cytokines (Il-6, Il-8, and CxCL4) and similar levels of DNA oxidative biomarkers. HFD moderately altered serum (3-nitrotyrosine and methionine/homocysteine) and peritoneal (reduced glutathione/oxidized glutathione) pro-oxidative status but had no effect on peritoneal inflammatory (tumor necrosis factor α and tumor necrosis factor receptor 1) mediators. Results indicate that lesion genotype modifies dietary effects on disease establishment and/or progression and if translated, could be important for provision of nutritional guidelines to women with predisposition to, or affected by endometriosis.

Highlights

Endometriosis is a debilitating, estrogen-dependent disease that affects ~10% of reproductive-aged women (Burney and Giudice, 2012) and to a lesser extent (2–5%), post-menopausal women on hormone therapy (Secosan et al, 2020)
To determine the effects of high-fat diet (HFD) intake in an immunocompetent mouse model of endometriosis, ectopic lesions were established from syngeneic C57BL/6 J mouse endometrium
Recipients assigned to either CD (n = 7) or HFD (n = 9) beginning at postnatal day 21 (PND 21) were ip injected at PND 56 with same amounts of minced endometrial fragments (40 μg in 400 μl PBS) isolated from 8-week old CD-fed WT mice, following previously established protocols (Heard et al, 2016)

Summary

Introduction

Endometriosis is a debilitating, estrogen-dependent disease that affects ~10% of reproductive-aged women (Burney and Giudice, 2012) and to a lesser extent (2–5%), post-menopausal women on hormone therapy (Secosan et al, 2020). Extensive research to understand the pathogenesis of endometriosis suggests the involvement of multiple predisposing genetic aberrancies, a number of which have been experimentally evaluated in mouse models and further confirmed for presence in human lesions (Hirota et al, 2008; Heard et al, 2014; Burns et al, 2018; Han et al, 2019). These genes include those involved in immune, angiogenic, steroid hormone signaling, apoptotic, and proliferative pathways (Kim et al, 2014; Brown et al, 2018). While these findings necessitate confirmation in a larger population, they reveal significant genetic and environment interactions in disease development

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